Review article

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REVIEW ARTICLE

Serotonin and hypothalamic control of hunger: a review

F

ernanda

 

de

 M

atos

 F

eijó

1

, M

arcello

 c

asaccia

 B

ertoluci

2

, c

íntia

 r

eis

3

1 

M. Sc. in Medicine - Medical Sciences, Universidade Federal do Rio Grande do Sul – UFRGS, Porto Alegre, RS

2 

Ph.D in Medicine - Medical Sciences, UFRGS; Associate Professor, Department of Intern Medicine, UFRGS; Professor, Medical Science Post-Graduation Program, UFRGS; Post-

Graduation Program Coordinating Committee Member, UFRGS, Porto Alegre, RS

3 

M. Sc. in Medicine - Medical Sciences, UFRGS, Porto Alegre, RS

From Medicine Postgraduation 

Program: Medical Science 

School, Universidade Federal 

do Rio Grande do Sul (UFRGS); 

Department of Intern Medicine, 

Hospital de Clínicas de Porto 

Alegre, Porto Alegre, RS, Brazil

Submitted on: 09/09/2010

Approved on: 11/02/2010

Corresponding author:

Fernanda de Matos Feijó

R. Tamandaré, 1020 ap. 210

CEP 91900-790

Porto Alegre, RS

Phone: [phone]

[e-mail]

Conflict of interest: None.

A

bstrAct

This paper reviews the involvement of the serotonergic system in controlling food intake 

and satiety. It is of great interest to understand this system relevance in physiologic con-

trol of energy balance and obesity. Over 35-year research suggests that serotonin (5-HT) 

plays an important role in satiety. Thus, serotonergic system has been a viable target in 

weight control. 5-HT shows control over hunger and satiety through different receptors 

with discrete functions. 5-HT2C receptor seems to be the most important one in the 

relationship between food intake and energy balance. In this review, serotonergic system 

mechanisms involved in food intake control and satiety will be discussed.

Keywords: Serotonin; serotonin 5-HT2C receptor; appetite regulation; satiety response; 

hypothalamus.

74

---

S

erotonin

 

and

 

hypothalamic

 

control

 

of

 

hunger

: 

a

 

review

75

Rev Assoc Med Bras 2011; 57(1):74-77

I

ntroductIon

Serotonin (5-HT) plays an important role in nervous sys-

tem with different functions, such as some hormone re-

lease, sleep, body temperature, and appetite regulation, 

mood, motor activity, and cognitive functions. Changes in 

levels of 5-HT (low levels or disturbed receptor signaling) 

have been related to increased craving for sweets and car-

bohydrates. If a person has a normal 5-HT level, he/she 

can achieve satiety and control over sugar intake more ea-

sily. This neurotransmitter proper level in the brain depen-

ds on food tryptophan (serotonin precursor amino acid) 

and carbohydrate intake

1-3

.

Over 35-year research suggests that 5-HT plays an im-

portant role in satiety. Thus, serotonergic system has been 

a viable target in weight control. Drugs inhibiting 5-HT 

uptake have been increasingly used to achieve weight loss 

in obesity treatment, as they enhance satiety power in food 

post-intake and post-absorption components. Several se-

rotonin receptor subtypes were identified, with 5-HT1B 

and 5-HT2C being recognized as satiety inductors

3-6

. Our 

aim is to review the role of brain serotonergic system in 

controlling food intake and satiety.

 

s

erotonergIc

 

system

5-HT or 5-hydroxytryptamine is an indolamine, a hydro-

xylation and carboxylation by-product of amine acid tryp-

tophan. It is produced in raphe nuclei and 

 

released throu-

ghout the brain. 5-HT is a neurotransmitter and as such, 

it serves to lead the transmission from one cell (neuron) 

to another. 5-HT is secreted by serotonergic neurons and 

exerts its activity on postsynaptic neuron receptors

7-9

.

Concentrations of brain 5-HT are related to behavior 

and mood changes, anxiety, aggressiveness, depression, 

sleep, fatigue, and even appetite suppression

7,10

.

5-HT has a behavior inhibiting effect, as well as a gen-

eral modulating effect on psychic activity. Therefore, 5-HT 

influences almost all brain functions by either inhibiting 

or stimulating gamma-aminobutyric acid (GABA). This 

is how 5-HT regulates mood, sleep, sexual activity, appe-

tite, circadian rhythm, neuroendocrine functions, body 

temperature, pain sensitivity, motor activity, and cognitive 

functions

7,8

.

The carrier of 5-HT (5-HTT) is responsible for reup-

take of 5-HT in serotonergic nervous endings. Studies 

have shown that inhibition of 5-HTT, by increasing 5-HT 

postsynaptic stimulation, reduces food intake and body 

weight gain in rats and humans

11,12

.

F

ood

 

neuromodulAtIon

A number of peptides act as neurotransmitters or hormo-

ne peptides by either increasing or reducing food intake. 

Feeding is also under a central system control regulated 

by a delicate balance between monoamines and neuro-

peptides

13-15

. Levels and possible functions of several neu-

rotransmitters are influenced by dietary precursor stores. 

Main neurotransmitters include biogenic amines (5-HT, 

dopamine, noradrenaline, histamine), formed from tryp-

tophan, tyrosine, and histidine, as well as acetylcholine 

and glicine, which can be constituted from choline and 

threonine. The effects of precursors may be sufficient to 

influence mood and behavior in some circumstances, and 

administration of purified dietary components is a partial 

means to alter the metabolism of neurotransmitters in ex-

perimental or therapeutic procedures in animals and hu-

mans

7,13,14

.

5-HT activity, also involved in food intake behavior 

modulation, is assessed through level measurement of its 

major metabolite, 5-hydroxyindolacetic acid (5-HIAA). In 

patients with anorexia nervosa, 5-HT concentration is re-

duced, while in treated patients it is above average values 

in controls. Reduced 5-HT could be related to reduced es-

sential amine acid intake, including tryptophan, as well as 

reduced serotonergic receptor (5-HT2C) sensitivity

14,15

.

Animal studies suggest that 5-HT is also involved in 

food intake control, with serotonin high levels reducing 

total energy intake or selectively reducing carbohydrate 

selection over protein

3,13

.

Among various species, in different experimental con-

ditions, there is strong evidence that the increased activ-

ity of postsynaptic serotonergic receptors  subsequently 

causes reduction in food intake over a meal and changes 

the feeding pattern. The same evidence is available for 

5-HT anorectic role, particularly as a response to unbal-

anced amine acid diets

13,16,17

.

If 5-HT level is normal, the subject is more easily satiate 

and sugar intake is more easily inhibited, he/she feels more 

easily full and has a better control over sweet craving

3,8,18

.

Drugs that inhibit the uptake of neurotransmitters 

5-HT allowing them to remain in greater quantities and 

for a longer time in the synaptic cleft promote a greater 

feeling of satiety and, in experimental studies, demon-

strate increased basal metabolism. Drugs as sibutramina, a 

satiety agent providing better hunger control (notably for 

sweets), are increasingly used in weight loss diets. Drugs 

inhibiting serotonin uptake selectively, such as fluoxetine 

and sertraline, also reduce food intake, but they are not 

indicated in obesity treatment because of their nonspecific 

effect in reducing weight and weight regaining is observed 

in long-term studies

6,17-19

.

5-Ht 

pHysIologIcAl

 

Aspects

 

In

 

Food

 

IntAke

 

And

 

sAtIety

5-HT exhibits control over hunger and satiety through 

several receptors with different functions. There are seven 

different families of 5-HT receptors, and in some of these 

families there are many receptor subtypes, mainly 5-HT1 

and 5-HT2 receptors. These receptors are responsible 

for the reduced food intake associated with serotonergic  

---

f

ernanda

 

de

 m

atoS

 f

eijó

 

et

 

al

.

76

Rev Assoc Med Bras 2011; 57(1):74-77

agonist injection in paraventricular nucleus using quipazine, 

meta-chlorophenylpiperazine, and d-norfenfluramine

20-27

.

5-HT2C receptor seems to be the most important in 

the relationship between food intake and energy balance. 

Mice devoid of that gene become obese and epileptic, 

whereas agonists acting on 5-HT2C receptor produce re-

duced food intake

5,21-26

.

Acting via 5-HT2C receptor, 5-HT directly acti-

vates pro-opiomelanocortin (POMC) cleavage. Through 

5-HT1B receptor, serotonin hyperpolarizes and inhibits 

the neuropeptide Y (NPY) and the agouti-related protein 

(AgRP) at the arcuate nucleus, depressing gabaergic in-

hibiting transmission of a-melanotropin (a-MSH) and the 

cocaine and amphetamine regulated transcript (CART). 

These associated mechanisms produce satiety and thermo-

genesis stimulation and that is why these receptors have 

been investigated as pharmacotherapeutic goals in obesity 

treatment

17,30-32

.

5-HT, through 5-HT1B receptor action, modulates 

endogenous release of both agonists and antagonists of 

melanocortin receptors, which are a part of the major 

components of body weight homeostasis control circuit. 

Melanocortin pathway is essential for hypophagia in sero-

tonergic compounds. Recent research have clarified that 

melanocortina receptors 4 (MC4) are the key influencing 

appetite

3,17,23,33

.

5-HTC2 receptor agonist BVT.X reduces signifi-

cantly food intake without changing locomotor activity 

or oxygen consumption in obese and lean rats. Extend-

ed BVT.X infusion in obese rats increases significantly 

POMC mRNA and reduces body weight, body fat, and 

food intake. Mice lacking MC4 were used to assess mel-

anocortina functional importance in BVT.X effect on 

food behavior. The animals did not show any sensitivity 

to BVT.X-induced hypophagia, demonstrating MC4 re-

ceptor is a 5-HT2C agonist-depending pathway exerting 

effects on food intake. Extended BVT.X treatment pro-

motes weight loss and reduced body fat

3,31

.

The cannabinoid system also shows an interaction 

with serotonergic system. These systems can synergisti-

cally modulate food behavior. Further studies character-

izing 5-HT and cannabinoid receptor 1 (CB1) are required 

to identify mechanisms underlying interactions between 

cannabinoid and serotonergic systems

5

.

More recently, 5-HT2C receptor role in glucose ho-

meostasis was also reported in rodents. Pharmacological 

and genetic studies have shown direct 5-HT2C effects on 

glucose homeostasis. Serotonin uptake inhibitor-treated 

rats were demonstrated to have glucose tolerance im-

provement. The interaction between serotonin and leptin 

in glucose homeostasis makes serotonergic system a possi-

ble target in diabetes mellitus and obesity management

34-36

.

In conclusion, the serotonergic system shows control 

over hunger and satiety through various receptors with 

different functions. 5-HT2C receptor seems to be the most 

important receptor in the relationship between food in-

take and energy balance. This system is clearly important 

in controlling food intake and satiety and its evident syn-

ergistic interaction between different pathways, specifi-

cally 5-HT2C, POMC, and MC4, in regulating the energy 

balance.

r

eFerences

1.  Naves A, Paschoal V. Regulação Funcional da Obesidade. Com Sci-

entiae Saúde 2007; 6(1):189-199.

2.  Lam DD, Heisler LK. Serotonin and EnergyBalance: Molecular 

Mechanisms and Implications for Type 2 Diabetes. Expert Reviews 

in Molecular Medicine 2007; 9(5):1-24.

3.  Lam DD, Przydzial MJ, Ridley SH, Yeo GSH, Roshford JJ, O`Rahilly 

S, et al. Serotonin 5-HT2C Receptor Agonist Promotes Hypophagia 

via Downstream Activation of Melanocortin 4 Receptors. Endocri-

nology 2008; 149(3):1323-1328.

4.  Blundell JE. Serotonin and the Biology of Feeding. Am J Clin Nutr 

1992; 55(1 Suppl):155S-9S.

5.  Ward SJ, Lefever TW, Jackson C, Tallarida RJ, Walker EA. Effects of a 

Cannabinoid 1 Receptor Antagonist and Serotonin 2C Receptor Ag-

onist Alone and in Combination on Motivation for Palatable Food: 

Dose-Addition Analysis Study in Mice. The Journal of Pharmacol-

ogy and Experimental Therapeutics 2008; 325:567-576.

6.  Ferreira L, Gomes E.Estudo Sobre a Eficácia do Uso de Inibidores da 

Recaptação de Norepinefrina e Serotonina no Tratamento da Obesi-

dade. Revista Saúde e Pesquisa 2009; 2(3):363-369.

7.  Rossi L, Tirapegui J.Implicações do Sistema Serotoninérgico no Ex-

ercício Físico. Arq Bras Endocrinol Metab 2004; 48(2):227-233.

8.  Ballone GJ-Serotonina- in. PsiqWeb, Internet, disponível em www.

psiqweb.med.br, revisto em 2005.

9.  Ribeiro EB.Studying the Central Control of Food Intake and Obesity 

in Rats. Rev Nutr 2009; 22(1):163-171.

10.  Bell C, Abrams J, Nutt D. Tryptophan Depletion and its Implications 

for Psychiatry. Br J Psyc 2001; 178:399-405. 

11.  Petrisic MS, Augood SJ, Bicknell RJ. Monoamine transporter gene 

expression in the central nervous system in diabetes mellitus. Journal 

of Neurochemistry 1997; 68:2435-441.

12.  Olivier B, Oorschot R V. 5-HT1B Receptors and Aggression: A Re-

view. Eur J Pharmacol 2005; 526(1-3):207-17.

13.  Cambraia RPB. Aspectos Psicobiológicos do Comportamento Ali-

mentar. Rev Nutr 2004; 17(2):217-225.

14.  Hermsdorff HHM, Vieira MAQM, Monteiro JBR. Leptina e sua In-

fluência na Patofisiologia de Distúrbios Alimentares. Rev Nutr 2006; 

19(3):369-379.

15.  Yakabi K, Kurosawa S, Tamai M Yuzurihara M, Nahata M, Ohno S, 

et al. Rikkunshito and 5-HT2C receptor antagonist improve cispl-

atin-induced anorexia via hypothalamic ghrelin interaction. Regu-

Regu-

latory Peptides 2010; 161:97-105, 

16.  Luras A. Estudo de Fatores Centrais e Periféricos Relacionados 

ao Controle da Ingestão Alimentar em Modelos Experimentais. 

Ensaios e Ciências: C. Biológicas, Agrárias e da Saúde 2009; 13 

(1):19-27.

17.  Garfield AS, Heisler LK. Pharmacological Targeting of the Se-

Pharmacological Targeting of the Se-

rotonergic System for the Treatment of Obesity. J Physiol 2009; 

587(1):49-60.

18.  Simpson KA, Martin NM, Bloom SR. Hypothalamic Regulation of 

Food Intake and Clinical Therapeutic Applications. Arq Bras Endo-

crinol Metab  2009; 53(2):120-128.

19.  Garfield AS and Heisler LK.Pharmacological targeting of the se-

rotonergic system for the treatment of obesity. J Physiol 2009; 

587(1):49-60.

20.  Mancini MD, Halpern A. Aspectos Fisiológicos do Balanço Energé-

tico. Arq Bras Endocrinol Metab 2002; 46(3):230-248.

21.  Bickerdike MJ. 5-HT2C Receptor Agonists as Potential Drugs for the 

Treatment of  Obesity. Current Topics in Medicinal Chemistry 2003;  

3:885- 897.

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S

erotonin

 

and

 

hypothalamic

 

control

 

of

 

hunger

: 

a

 

review

77

Rev Assoc Med Bras 2011; 57(1):74-77

22.  Miller KJ. Serotonin 5-HT2C Receptor Agonists: Potential for the 

Treatment of Obesity. Mol Interv 2005; 5(5):282-91.

23.  Heisler LK, Jobst EE, Sutton GM, Zhou L, Borok E, Thornton-Jones 

Z,  et al. Serotonin Reciprocally Regulates Melanocortin Neurons to 

Modulate Food Intake. Neuron 2006; 51(2):239-49.

24.  Halford JC, Harrold JA, Boyland EJ, Lawton CL, Blundell JE. Seroto-

Seroto-

nergic Drugs: Effects on Appetite Expression and Use for the Treat-

ment of Obesity. Drugs 2007; 67(1):27-55. 

25.  Heisler LK, Pronchuk N, Nonogaki K, Zhou L, Raber J, Tung L, et 

al.  Serotonin Activates the Hypothalamic-Pituitary-Adrenal Axis 

via Serotonin 2C Receptor Stimulation. The Journal of Neuroscience 

2007; 27(26):6956-6964.

26.  Canal CE, Mahautmr KC, Cao C, Bush ES and Airey DC. RNA ed-

iting of the serotonin 2C receptor and expression of Gαq protein: 

genetic mouse models do not support a role for regulation or com-

pensation. J Neurochem  2009; 108(5): 1136-1142.

27.  Tarazi FI, Moran-Gates T, Wong EHF, Henry B, Shahid M. Asenap-

ine induces differential regional effects on serotonin receptor sub-

types. J Psychopharmacol 2010; 24(3): 341-348. 

28.  Baez M, Kursar JD, Helton LA, Wainscott DB, Nelson DLG. Molecu-

lar biology of serotonin receptors. Obes Res 1995; 3(Suppl.):4415-75. 

29.  Smith BK, York DA, Bray GA. Activation of hypothalamic serotonin 

receptors reduced intake of dietary fat and protein but not carbohy-

drate. Am J Physiol 1999; 277:802-11.   

30.  Serpa NA, Saheb GCB, Arantes BS, Pedralli JJ, Silva RBS, Buriti NA. 

Fatores Ambientais, Comportamentais e Neuroendocrinológicos 

Envolvidos na Gênese da Epidemia da Obesidade. Arq Bras de Ciên-

cias da Saúde 2007; 33(1):44-53.

31.  Qiu J, Xue C, Bosch MA, Murphy JG, i Fan W, Rønnekleiv OK, Kelly 

MJ. Serotonin 5-Hydroxytryptamine2C Receptor Signaling in Hypo-

Serotonin 5-Hydroxytryptamine2C Receptor Signaling in Hypo-

thalamic Proopiomelanocortin Neurons: Role in Energy Homeosta-

sis in Females. Mol Pharmacol 2007; 72:885-896.

32.  Xu Y, Jones EJ, Kohno D, Williams KW, Lee CE, Choi MJ, et al. 

5-HT2CRs Expressed by Pro-Opiomelanocortin Neurons Regulate 

Energy Homeostasis. Neuron 2008; 26; 60(4-2):582-589.

33.  Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, et al. 

Activation of Central Melanocortin Pathways by Fenfluramine. Sci-

ence 2002; 297(5581):609-611.

34.  Marston OJ, Heisler LK. Targeting the Serotonin 2C Receptor for the 

Treatment of Obesity and Type 2 Diabetes. Hot Topics Neuropsycho-

pharmacology 2009;  34:252-253.

35.  Wade JM, Juneja P, MacKay AW, Graham J, Havel PJ, Tecott LH, 

Goulding EH. Synergistic Impairment of Glucose Homeostasis in 

ob/ob Mice Lacking Functional Serotonin 2C Receptors. Endocrino-

log 2008; 149(3):955-961.

36.  Bechtholt AJ, Smith K, Gaughan S, Lucki I. Sucrose Intake and Fast-

ing Glucose Levels in 5-HT1A and 5-HT1B Receptor Mutant Mice. 

Physiol Behav 2008; 18, 93(4-5): 659-665.